LEUKOTRIENES AND THE BLOOD-BRAIN BARRIER

LTC4在人脑肿瘤中的表达与其含量有关 肿瘤周围的水肿症。人脑肿瘤表达花生四烯酸5- 脂氧合酶mRNA和5-脂氧合酶的抑制作用将降低 肿瘤中血脑屏障(BBB)的通透性。白三烯(LT)C4 将选择性地打开肿瘤中的血肿瘤屏障(BTB)两倍 而不会增加正常大脑的渗透率。在…的基础上 这些发现表明，白三烯可能允许 增加了抗肿瘤药物对肿瘤组织的输送。相反， 抑制5-脂氧合酶可减轻脑瘤水肿。至 进一步研究白三烯和酶BBB的概念：1A) 脑瘤大鼠脑血流量和血流量的变化 颈动脉(IC)注射白三烯后的体积将被量化； 和1B)将使用电子显微镜来确定 LT增加血脑屏障通透性的机制是通过紧闭 连接或增加胞饮转运。2a)识别另一个 “酶屏障”中可能存在的酶，二肽酶的抗血清( 将LTD4转化为LTE4的酶)用于确定 二肽酶存在于大鼠和人脑毛细血管中，如果是这样的话， 无论是在脑瘤还是脑缺血中丢失。2b)对 酸性蛋白对LTC4的GGTP抑制作用 开张情况将另行决定。进一步理解“酶的作用” 屏障，3A)其他血管活性化合物，缓激肽和组胺， 也可以允许选择性的BBB打开将单独和在 与白三烯联合，有或没有组胺H1和H2 受体阻滞剂和5-脂氧合酶抑制剂。3B)这些措施的影响 将测定化合物对脑血容量的影响。3C)电子 显微镜也将被用来确定增加的机制 渗透性。3D)通过这些将BBB打开到不同大小的分子 化合物将被测定。4)5-脂氧合酶转录本将 进一步表现为人脑肿瘤的特点。5)研究将确定 实验性肿瘤治疗后对药物的通透性是否增加 颈动脉内输注白三烯和其他血管活性化合物。

There is a correlation between LTC4 in human brain tumors and the amount of edema surrounding tumors. Human brain tumors express arachidonate 5- lipoxygenase mRNA and the inhibition of 5-lipoxygenase will decrease blood-brain barrier (BBB) permeability in tumors. Leukotriene (LT) C4 will selectively open the blood-tumor barrier (BTB) in tumors two-fold without increasing permeability in the normal brain. On the basis of these findings we have suggested that leukotrienes could allow for increased delivery of anti-tumor drugs to tumor tissue. Conversely, inhibition of 5-lipoxygenase could reduce brain tumor edema. To investigate further leukotrienes and the concept of an enzymatic BBB: 1A) in rats with brain tumors, changes in cerebral blood flow and blood volume after intracarotid (IC) leukotriene infusions will be quantitated; and 1B) electron microscopy will be used to determine whether the mechanism by which LT's increase BBB permeability, is by opening tight junctions or increasing pinocytic transport. 2A) To identify another possible enzyme in the "enzymatic barrier," antiserum to dipeptidase (the enzyme that converts LTD4 to LTE4) is used to determine whether dipeptidase is present in rat and human brain capillaries, and if so, whether it is lost in brain tumors or ischemia. 2B) The dose response to gamma glutamyl transpeptidase (gGTP) inhibition by acivicin to LTC4 opening will be determined. To further understand the "enzymatic barrier," 3A) other vasoactive compounds, bradykinin and histamine, that may also allow selective BBB opening will be infused IC alone and in combination with leukotrienes, with and without histamine H1 and H2 receptor blockers and 5-lipoxygenase inhibitors. 3B) The effect of these compounds on cerebral blood volume will be determined. 3C) Electron microscopy will also be utilized to determine the mechanism of increased permeability. 3D) Opening of the BBB to different size molecules by these compounds will be determined. 4) 5-lipoxygenase transcripts will be further characterized in human brain tumors. 5) Studies will determine whether permeability to drugs is increased in experimental tumors after intracarotid infusion of leukotrienes and other vasoactive compounds.